EP0758245B1 - Use of spiramycin for treating gastrointestinal disorders caused by h. pylori - Google Patents

Abstract

PCT No. PCT/FR95/00533 Sec. 371 Date Oct. 22, 1996 Sec. 102(e) Date Oct. 22, 1996 PCT Filed Apr. 24, 1995 PCT Pub. No. WO95/28943 PCT Pub. Date Nov. 2, 1995Gastrointestinal disorders involving Helicobacter pylorid are treated by administering spiramycin or spiramycin/metronidazole combinations. In addition, administration of anti-ulcer agents may be carried out before, during or after such administration of spiramycin or spiramycin/metronidazole combinations. Pharmaceutical compositions for such administrations are also disclosed.

Description

The present invention relates to a new therapeutic application spiramycin possibly in combination with metronidazole.

Spiramycin optionally in combination with metronidazole may be useful for the preparation of a medicament intended for the prevention or treatment of gastrointestinal disorders in which Helicobacter pylori intervenes .

Many cases of peptic ulcers are identified each year. These ulcers are usually treated with anti-ulcer agents such as anti-H ₂ , bismuth derivatives or proton pump inhibitors. However, these are long-term treatments which are very expensive, difficult for patients to accept and in which numerous relapses are observed.

Helicobacter pylori, isolated for the first time from the gastric mucosa in 1982, is responsible for gastropathies such as gastritis and peptic ulcers, and probably also at the origin of the appearance of gastric cancers. The eradication of Helicobacter pylori largely modifies the importance of ulcerative diseases. Not only do ulcers disappear quickly (around 90%), but relapses are almost completely eliminated.

Treatments to eradicate Helicobacter pillory by means of compositions comprising an antibacterial and an anti-ulcer agent are already mentioned in patent applications EP 206 625, EP 282 131, WO 92/04 898 and WO 93/21 920.

However, many publications report demonstrations of intolerance which appear in 20 to more than 40% of patients, mostly consisting of nausea and diarrhea, but also abdominal pain. These side effects come from the nature of the products currently used in the clinic, doses which should be administered and the duration of treatment.

In addition, the majority of effective therapies consist of administration of 3 drugs, which is not well accepted by patients. Thus the practitioner is faced with the difficult choice between the power of the treatment, the limitation of side effects and the patient's poor acceptance of such medication.

Spiramycin is a well-known antibacterial agent, isolated from Streptomyces ambofaciens : US 2,943,023, US 2,978,380 and US 3,011,947.
Metronidazole is a derivative of nitro imidazole also known (US 2,944,061) and endowed with a parasiticidal and antibacterial action.
The spiramycin / metronidazole combination marketed under the name Rodogyl® is known for its action on anaerobic germs of the oral flora.

However, the activity of spiramycin or its associations with metronidazole did not suggest that an action could be observed in the clinic on a germ that is difficult to eradicate such as Helicobacter pylori for which it is usually necessary to use much more powerful antibacterials , with the consequences that we know.

It has now been shown that it is possible to obtain the eradication of Helicobacter pylori by administration of spiramycin or of a spiramycin / metronidazole combination, with a rate of side effects quite reduced compared to the other treatments.

Administration takes place before, after or simultaneously with administration of an anti-ulcer agent

The anti-ulcer agents are chosen indifferently from antacids, anti H ₂ and proton pump inhibitors.

The antacids can in particular be derivatives of bismuth or combinations of aluminum hydroxide and magnesium hydroxide like Maalox®.

The anti-H ₂ agents can be, for example, ranitidine, cimetidine, famotidine .....

Proton pump inhibitors can be for example omeprazole, lansoprazole, pantoprazole ....

Among the spiramycin / metronidazole associations, more particularly preferred is the association that makes up Rodogyl® (association 750,000 I.U. spiramycin base / 125 mg metronidazole). This association pre-existing allows in addition to administer only one antibacterial specialty during treatment.

The activity was demonstrated in a 10-day treatment in patients with peptic ulcers.

inclusion : hommes et femmes de 18 à 80 ans motivés, souffrant d'ulcère bénin duodénal ou gastrique vérifié par endoscopie haute et ayant subi un test positif d'uréase à partir de tissu prélevé par biopsie, préalablement au traitement [G. Nysaeter, K. Berstad et coll., Tidsskr Nor Laegeforen, 112, 2397-9 (1992)];

exclusion : patients risquant de présenter des risques d'allergie à l'un des médicaments administrés, femmes enceintes ou sans contraception, patients présentant d'autres maladies gastrointestinales risquant de modifier l'interprétation du test, ainsi que patients recevant un autre anti-ulcère au moment de l'inclusion dans l'étude ou ayant rechuté après un traitement préalable en vue d'éradiquer Helicobacter pylori.

25 patients with peptic ulcers were included according to the following criteria:

inclusion: motivated men and women aged 18 to 80, suffering from benign duodenal or gastric ulcer verified by upper endoscopy and having undergone a positive urease test using tissue removed by biopsy, prior to treatment [G. Nysaeter, K. Berstad et al., Tidsskr Nor Laegeforen, 112 , 2397-9 (1992)];

exclusion: patients at risk of allergy to one of the administered drugs, pregnant women or women without contraception, patients with other gastrointestinal diseases who may change the interpretation of the test, as well as patients receiving another anti-ulcer at the time of inclusion in the study or having relapsed after prior treatment with a view to eradicating Helicobacter pylori.

TREATMENT :

Spiramycin (Rovamycine®) 1,500,000 IU and 150 mg of sub-nitrate of bismuth in the form of a 1.5% solution (10 ml) are administered every 2, 4 times a day (a total of 6 million iu. spiramycin and 600 mg bismuth sub-nitrate). 400 mg metronidazole (Flagyl®) are given 3 times a day. The same treatment is continued for 10 days, spiramycin and metronidazole are given during meals and bismuth between meals. During the following weeks, patients are not given no other anti-ulcer medication.

A questionnaire concerning side effects was given to each patient. The questionnaire is identical to that given in previous Helicobacter pylori eradication studies [K. Berstad et al., Is there a place for antacids in treatment of Helicobacter pylori infection ?, Scand. J. Gastroenterol., 27 , 1006-1010 (1992)]. Side effects have been classified as "mild" (does not limit usual daily activities), "moderate" (limit daily activities to some extent) and "severe" (make daily activities impossible).

Eradication of Helicobacter pylori and healing of ulcers:

A breath test and a new endoscopy are performed 4 weeks after stopping treatment. In the event that an ulcer is detected, treatment will be considered a failure and the patient will receive conventional treatment. Urease tests using biopsy tissue and ¹⁴ C urea breathing [K. Bergstad et al., Biometric evaluation of gastric urease activity in man, Scand. J. Gastroenterol., 27 , 977-83 (1992)] are produced.

RESULTS:

2 patients who refused one to continue treatment until the end, the other to submit to the tests, are excluded from the study. The results below concern the 23 other patients.

7 women and 16 men of average age 53.9 years (ranging from 31 to 81 years) were included, in whom the disease had lasted an average of 18.7 years, namely from 1 to 40 years depending on the case. 19 of them previously had a peptic ulcer verified by endoscopy. 5 had previously been operated on for ulcers and 5 had previously been hospitalized for peptic ulcer accompanied by bleeding.

At the time of inclusion 10 patients had a declared duodenal ulcer, 7 had a gastric ulcer and 1 had a pyloric ulcer. 5 patients had duodenitis or gastritis, but with healed ulcers. These last 5 patients had undergone intermittent treatment with an anti-H ₂ . All of the patients had dispeptic symptoms and a positive urease test from biopsy tissue.

Healing ulcers:

4 weeks after treatment 21 of 23 patients no longer had ulcers. The healing rate is 91.3% (range of confidence 72.0 to 98.9%).

Eradication of Helicobacter pylori:

20 patients obtained a negative ¹⁴ C-urea breath test, indicating the eradication of Helicobacter pylori. Either an eradication rate of 87.0% (confidence interval 66.4 to 97.2%). There was perfect agreement between the urease test and the breath test, with the exception of one patient.

Side effects :

Of the patients who took treatment until the end, 4 were with nausea, 16 with diarrhea and 4 with abdominal pain. However overall the side effects have been classified as "light" ie not disturbing daily activities usual, except for only 2 patients for whom the effects were considered "severe".

It was thus possible to obtain rates of eradication of Helicobacter pylori and of healing of ulcers similar to the rates of the best treatments, but with a treatment of shorter duration than for certain known treatments and especially largely reduced side effects since only 2 out of 24 patients experienced side effects that affected their normal daily activity. (In similar studies, by administration of other antibacterials moderate to severe diarrhea had been observed in 41.5% of patients which is considerably higher than 1 in 23, or 4.4% in the present study).

The present invention also relates to pharmaceutical compositions comprising spiramycin optionally in combination with metronidazole, intended for the prevention or treatment of gastrointestinal disorders in which Helicobacter pylori intervenes .

As compositions for oral administration, can be used tablets, capsules, pills, lyophilisate powders or granules. These compositions may contain the active principle (s) in a pure state or possibly in combination with one or more compatible diluents, lubricants or adjuvants and pharmaceutically acceptable.

By way of example, the compositions may contain excipients such as starch, dextrin, gelatin, polyvinylpyrrolidone, hydrated alumina, hydrated silica, dicalcium phosphate, magnesium stearate, sorbitol, mannitol, lactose, sucrose, citric acid ....

It is understood that the doctor will adjust the dosage to the subject treat. More particularly the daily dosage can be between 0.75 and 10 million IU of spiramycin possibly in combination with 125 to 1500 mg of metronidazole in 2 to 3 doses.

The compositions according to the invention will be used in all cases of prevention or treatment of gastrointestinal disorders in which Helicobacter pylori intervenes . Especially gastric ulcers, duodenal ulcers, esophageal ulcers, gastritis, pre-pyloric ulcers, non-ulcerative dyspepsia, gastric cancers.

Claims (5)

1. Use of spiramycin, optionally in combination with metronidazole, for the preparation of a medicinal product intended for the prevention or treatment of gastrointestinal disorders involving Helicobacter pylori.
2. Use of spiramycin, optionally in combination with metronidazole, for the preparation of a medicinal product intended for the prevention or treatment of gastrointestinal disorders involving Helicobacter pylori, the said treatment being carried out before, after or at the same time as the treatment with an anti-ulcer agent.
3. Pharmaceutical composition containing spiramycin in combination with metronidazole, for a use according to Claim 1 or 2.
4. Pharmaceutical composition according to Claim 3, containing an anti-ulcer agent and spiramycin, optionally in combination with metronidazole.
5. Pharmaceutical composition according to Claim 4, characterized in that the anti-ulcer agent is chosen from antacids, anti-H₂ agents and proton pump inhibitors.